The applicant describes a five-year career development plan leading to independent academic investigations on the role of epigenetic mechanisms in aging of the hematopoietic system. While the applicant's previous research experience has involved quantitative analysis of biological systems, including investigations of epigenetic organization in model organisms, these computational studies have concentrated on general organization and regulatory principles of genome. The proposed research and training plan will allow the applicant to focus on a set of problems directly relevant to human health. The training will provide the applicant with necessary laboratory skills and in-depth knowledge of the hematopoietic system, age-associated pathologies and mechanisms involved in tissue homeostasis. The proposed research program will conduct experimental and quantitative analysis of age-associated epigenetic alterations affecting various stages of hematopoiesis in a mouse model, providing an important starting point for further targeted investigations of age-linked pathologies, and allowing the applicant to establish himself as an independent scientist in this field. Advanced age is a major risk factor contributing to heart disease, cancer and other leading causes of deaths in the United States. Aging is associated with progressive functional decline of multiple organ systems and a widespread disruption of tissue functions. Changes in the hematopoietic tissues that accompany aging have significant detrimental impact on the individual's health, resulting in overall decline of the function of the immune system, increased incidence of autoimmune and myloproliferative diseases. The complex biological mechanisms underlying this progression remain poorly understood, but are known to involve changes in the epigenetic state at some levels of hematopoiesis. The proposed research will examine specific aspects of the epigenetic state, to determine the nature and scope of these changes, and the role they play in age-associated decline of hematopoietic tissues. The study will test for global alterations in the activity of epigenetic silencing mechanisms, in particular with respect to maintenance of heterochromatic regions. It will infer affected genes, epigenetic and regulatory pathways to construct integrative models of age-associated progression at different stages of hematopoiesis. The study will then use these results to identify the aspects of normal hematopoietic aging affected in animals under caloric restriction conditions that attenuate aging phenotypes. PUBLIC HEALTH RELEVANCE: Age-dependent changes in hematopoietic system, leading to compromised blood cell functions, result in reduced delivery of oxygen to all the tissues, immunodeficiency, autoimmune and myeloproliferative diseases. The complex biological mechanisms underlying these conditions remain poorly understood, but are known to involve changes in the epigenetic state, requiring further investigation. Understanding the molecular mechanisms of these epigenetic alterations in the hematopoietic system will be important for the development of prophylactic and therapeutic measures that could promote healthy aging.